N,N-di(aryl) cyclic urea derivatives as anti-coagulants

Abstract

N,N-di(aryl) cyclic urea derivatives, such as the compounds of the following formula: <IMAGE> (III) wherein R1 is -C(NH)NH2, -C(NH)N(H)OR11, -C(NH)N(H)C(O)R9, or -C(NH)N(H)C(O)OR11; R2 and R3 are independently hydrogen, halo, lower alkyl, lower haloalkyl, aryl, -OR11, -C(O)OR11, -C(O)N(R11)R12, -N(R11)R12, -N(H)C(O)R11, or -N(H)S(O)2R11; R4 is halo, lower haloalkyl, imidazolyl, -C(NH)NH2, -C(NH)NHOR11, -C(NH)N(H)C(O)R9, -C(NH)N(H)C(O)OR11, -OR11, -C(O)R13, -(CH2)nC(O)OR11 (where n is 0 to 6), -C(O)N(R11)R12, or -N(R11)R12; R7 and R8 are independently hydrogen, lower alkyl, lower haloalkyl, 4-pyridinyl, -C(O)OR11, -C(O)N(R11)R12, or aryl (optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and -N(R11R12); R11 and R12 are independently hydrogen, lower alkyl, aryl or lower aralkyl; or R13 is pyrrolidinyl, 4-morpholinyl, piperazinyl, N-methylpiperazinyl, or piperidinyl; or a pharmaceutically acceptable salt thereof, are disclosed herein as being inhibitors of factor Xa and thereby being useful as anticoagulants.

What is claimed is: 
     
       1. A compound selected from the group consisting of the following formulae: ##STR11## wherein: A is --C(R 5 )R 6  --(CH 2 ) m  --C(R 9 )(R 10 )-- (wherein m is 0 to 2); R 1  is --C(NH)NH 2 , --C(NH)N(H)OR 11 , --C(NH)N(H)C(O)R 9 , or --C(NH)N(H)C(O)OR 11  ;   R 2  and R 3  are the same or different and are selected from the group consisting of independently hydrogen, halo, lower alkyl, lower haloalkyl, phenyl, naphthyl, --OR 11 , --C(O)OR 11 , --C(O)N(R 11 )R 12 , --N(R 11 )R 12 , --N(H)C(O)R 11 , and --N(H)S(O) 2  R 11  ;   R 4  is halo, lower haloalkyl, --C(NH)NH 2 , --C(NH)N(H)OR 11 , --C(NH)N(H)C(O)R 9 , --C(NH)N(H)C(O)OR 11 , --OR 11 , --(CH 2 ) n  C(O)OR 11  (where n is 0 to 6), --C(O)N(R 11 )R 12 , or --N(R 11 )R 12  ;   R 7  and R 8  are independently hydrogen, lower alkyl, lower haloalkyl, --C(O)OR 11 , --C(O)N(R 11 )R 12 , phenyl (optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R 11 )R 12 ), or naphthyl (optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R 11 )R 12 );   R 9  and R 10  are independently hydrogen, halo, lower alkyl, lower haloalkyl, --OR 11 , --C(O)OR 11 , --C(O)N(R 11 )R 12 , phenyl (optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R 11 )R 12 ), or naphthyl (optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R 11 )R 12 ); and   R 11  and R 12  are independently hydrogen, lower alkyl, phenyl, naphthyl or lower aralkyl, or a pharmaceutically acceptable salt thereof.   
     
     
       2. The compound of claim 1 selected from formula (III) wherein: R 1  is --C(NH)NH 2 , --C(NH)N(H)OR 11  or --C(NH)N(H)C(O)OR 11  ;   R 2  and R 3  are the same or different and are selected from the group consisting of independently hydrogen, lower alkyl or --OR 11  ;   R 4  is --C(NH)NH 2 , --C(NH)N(H)OR 11 , --C(NH)N(H)C(O)OR 11  or --C(O)N(R 11 )R 12  or --N(R 11 )R 12  ;   R 7  and R 8  are independently hydrogen, lower alkyl, phenyl (optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R 11 )R 12 ), or naphthyl (optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R 11 )R 12 ); and   R 11  and R 12  are independently hydrogen, lower alkyl, phenyl or benzyl.   
     
     
       3. A pharmaceutical composition useful in treating a human having a disease-state characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound selected from the group consisting of the following formulae: ##STR12## wherein: A is --C(R 5 )R 6  --(CH 2 ) m  --C(R 9 )(R 10 )-- (where m is 0 to 2); R 1  is --C(NH)NH 2 , --C(NH)N(H)OR 11 , --C(NH)N(H)C(O)R 9 , or --C(NH)N(H)C(O)OR 11  ;   R 2  and R 3  are the same or different and are selected from the group consisting of independently hydrogen, halo, lower alkyl, lower haloalkyl, phenyl, naphthyl, --OR 11 , --C(O)OR 11 , --C(O)N(R 11 )R 12 , --N(R 11 )R 12 , --N(H)C(O)R 11 , and --N(H)S(O) 2  R 11  ;   R 4  is halo, lower haloalkyl, --C(NH)NH 2 , --C(NH)N(H)OR 11 , --C(NH)N(H)C(O)R 9 , --C(NH)N(H)C(O)OR 11 , --OR 11 , --(CH 2 ) n  C(O)OR 11  (where n is 0 to 6), --C(O)N(R 11 )R 12 , or --N(R 11 )R 12  ;   R 7  and R 8  are independently hydrogen, lower alkyl, lower haloalkyl, --C(O)OR 11 , --C(O)N(R 11 )R 12 , phenyl (optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R 11 )R 12 ), or naphthyl (optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R 11 )R 12 );   R 9  and R 10  are independently hydrogen, halo, lower alkyl, lower haloalkyl, --OR 11 , --C(O)OR 11 , --C(O)N(R 11 )R 12 , phenyl (optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R 11 )R 12 ), or naphthyl (optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy and --N(R 11 )R 12 ); and   R 11  and R 12  are independently hydrogen, lower alkyl, phenyl, naphthyl or lower aralkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.     
     
     
       4. The compound of claim 2 wherein: R 1  is --C(NH)NH 2  ;   R 2  and R 3  are independently hydrogen or --OR 11  ;   R 4  is --C(NH)NH 2  or --C(O)N(R 11 )R 12  ;   R 7  and R 8  are independently hydrogen, lower alkyl or phenyl (optionally substituted by one or more substituents selected from the group consisting of --OR 11  and --N(R 11 )R 12 ); and   R 11  and R 12  are independently hydrogen or lower alkyl.   
     
     
       5. The compound of claim 4 wherein: R 1  and R 4  are both --C(NH)NH 2  ;   R 2  and R 3  are both hydrogen;   R 7  and R 8  are independently phenyl optionally substituted by --OR 11  or --N(R 11 )R 12  ; and   R 11  and R 12  are independently hydrogen or lower alkyl.   
     
     
       6. The compound of claim 5 wherein R 7  and R 8  are both phenyl. 
     
     
       7. The compound of claim 6, namely, 3,3'-[(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl)bis(methylene)]bis(benzamidine). 
     
     
       8. The compound of claim 5 wherein: R 7  is phenyl; and   R 8  is 4-dimethylaminophenyl.   
     
     
       9. The compound of claim 8, namely, 3,3'-[[2,3-dihydro-4-(4-dimethylaminophenyl)-2-oxo-5-phenyl-1H-imidazol-1,3-diyl]bis(methylene)]bis(benzamidine). 
     
     
       10. The compound of claim 1 selected from formula (IV) wherein: R 1  and R 4  are both --C(NH)NH 2  ;   R 2  and R 3  are independently hydrogen or --OR 11  ;   R 7 , R 8  and R 9  are independently hydrogen, lower alkyl or phenyl (optionally substituted by one or more substituents selected from the group consisting of --OR 11  and --N(R 11 )R 12 ); and   R 11  and R 12  are independently hydrogen or lower alkyl.   
     
     
       11. The compound of claim 10 wherein: R 1  and R 4  are both --C(NH)NH 2  ;   R 2  and R 3  are both hydrogen;   R 7  and R 8  are both phenyl; and   R 9  is hydrogen.   
     
     
       12. The compound of claim 11, namely, 7-[[3-[4-(amidino)benzyl]-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl]methyl]-naphthalene-2-carboximidamide. 
     
     
       13. The compound of claim 11, namely, 7-[[3-[3-(amidino)benzyl]-2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl]methyl]naphthalene-2-carboximidamide. 
     
     
       14. The compound of claim 1 selected from formula (V) wherein: R 1  and R 4  are both --C(NH)NH 2  ;   R 2  and R 3  are independently hydrogen or --OR 11  ;   R 7 , R 8 , R 9  and R 10  are independently hydrogen, lower alkyl or phenyl (optionally substituted by one or more substituents selected from the group consisting of --OR 11  and --N(R 11 )R 12 ); and   R 11  and R 12  are independently hydrogen or lower alkyl.   
     
     
       15. The compound of claim 14 wherein: R 1  and R 4  are both --C(NH)NH 2  ;   R 2  and R 3  are both hydrogen;   R 7  and R 8  are both phenyl; and   R 9  and R 10  are both hydrogen.   
     
     
       16. The compound of claim 15, namely, 7,7'-[[2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1,3-diyl]bis(methylene)]bis(naphthalene-2-carboximidamide).